Despite intensive research on the neurobiological mechanisms of chronic pain, this therapeutic area remains one of the least satisfactorily covered by current drugs. Over one-third of the world's population suffers from persistent or recurrent pain, and untreated pain may become self-perpetuating, because pain has immunosuppressive effects that leave patients susceptible to subsequent diseases (C. L. Stuky, Mechanisms of Pain, PNAS, 2001, 98, 11845). Pain is defined by the International Association for the Study of Pain (IASP, Classification of chronic pain, 2nd Edition, IASP Press, 2002, 210) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage”. Even though pain is always subjective, its causes or syndromes can be divided into two categories, physiological pain and pathological or clinical pain. Physiological pain is acute and has a protective role that warns of potential tissue damage, while pathological pain is usually chronic. Pathological pain can be mainly divided into inflammatory pain, a kind of pain more related to peripheral tissue damage/inflammation, and neuropathic pain.
Neuropathic pain refers clinically to a group of chronic pain syndromes. These syndromes share the common feature that they are caused by an initial nerve damage which subsequently results in an abnormal sensory processing in the central and peripheral nervous system. Neuropathic pain conditions are the consequence of a number of diseases, for instance diabetes, cancer, amputees, multiple sclerosis.
Inflammatory pain is affecting hundreds of millions of people in the world. Although arthritis (being rheumatoid arthritis and osteoarthritis the most common form of arthritis) is defined as inflammation of the joint, the primary feature with which patients present in the clinic is chronic pain; even though arthritis is not the only pathology which can give rise to chronic pain, it is rather common and quite representative of this kind of pain.
Peripheral sensitization and central sensitization are two major mechanisms underlying the generation of pathological pain. When tissue damage occurs, an inflammatory response develops that triggers mechanisms in both the nervous and the immune system. This results in an ongoing painful state. During tissues injury and inflammation, sensitizing agents such as pro-inflammatory prostaglandins (PGE2), 5-HT, bradykinin, histamine, ATP, cytokines are released from inflammatory cells and nerve terminals. These mediators evoke activation of specific ion channels through the excitation of peripheral nociceptive neurons, involving activation of intracellular kinases, and resulting in peripheral sensitization. Activation of peripheral nociceptors also results in an activity or use dependent neuronal plasticity in the CNS. This plasticity modifies the performance of nociceptive pathway by enhancing and prolonging the responses to subsequent peripheral stimuli. These changes in the spinal cord, as well as in the brain are referred to central sensitization. Central sensitization plays a major role in maintaining elevated pain sensitivity and it is responsible for the pain produced after injury by normally innocuous low threshold afferent inputs. A so complex mechanism for pain induction and control can explain why the treatment of pain conditions has not found yet a satisfactory pharmacological solution.
Opiate drugs such as morphine are well known for their ability to produce potent analgesia as well as unwanted side effects, such as tolerance, physical dependence, respiratory suppression and constipation. In order to identify new agents for the clinical management of pain, several alternate pharmacological approaches have been carried out in the last decade, for example COX-2 inhibitors, displayed a good efficacy in the treatment of inflammatory pain, but lacked effectiveness in the treatment of neuropathic pain, in addition for COX-2 inhibitors undesirable life threatening side-effects were recently highlighted.
The available analgesics for the treatment of neuropathic pain, for instance some tricyclic antidepressant (e.g.: Amitriptyline) and a few antiepileptic drugs (e.g. gabapentin, lamotrigine, and carabamazepine) are effective in some patients, however there is still a large need for efficient drugs for neuropathic pain treatment.